The application "Quantitative optical imaging of molecular processes in preclinical cancer models" is submitted in response to the NCRR program announcement for the Special Emphasis Research Career Award (SERCA, K01) in Pathology and Comparative Medicine. It is becoming increasingly evident that no single imaging modality is capable of providing sufficient information for diagnosis, prognosis and therapeutic efficacy. The Candidate seeks to gain training in biomedical imaging to lead an independent research career applying advanced optical imaging methods and magnetic resonance imaging (MRI) to investigate the molecular mechanisms of cancer. Areas of specific career development training will include courses covering molecular biology of cancer, principles of magnetic resonance imaging and principles of biomedical imaging and contrast agent development. Principles of molecular imaging using cancer-targeted fluorescent probes, including characteristics of contrast agents (small molecules, macromolecules and nanoparticles) and targeting moiety (monoclonal antibodies, receptor-specific proteins, high affinity peptides and cleavable peptide sequences).The Candidate will receive instruction on the physical and physiologic basis of Magnetic Resonance Imaging and the experimental procedures for perfusion and diffusion weighted imaging and dynamic contrast-enhanced MRI, including methods and software for measuring and modeling pharmacokinetics of imaging agents, including elimination, tissue delivery and clearance, receptor binding and enzyme activity. These principles will be applied to develop complementary optical imaging methods with conventional and activatable molecular probes. The practical aspects of animal models of human cancer, including human cell and tissue xenografts, transgenic cancer models, for molecular imaging will also be included as a necessary component of the training and research. The Candidate will be mentored in scientific writing, including submission of scientific manuscripts, as well as grantsmanship with the goal of at least one R01-level application submitted in year 4. This training will take place at Washington University School of Medicine, a world leader in biomedical research, particularly biomedical imaging. The Candidate will be mentored by and collaborate with outstanding researchers in the fields of optical imaging, magnetic resonance imaging and cancer biology. Optical imaging is an excellent method for low cost, high-throughput preclinical imaging using safe and stable contrast agents. Rather than radioactive contrast agents, optical imaging uses fluorescent compounds that can be visualized throughout the body for days to weeks after injection with no evident toxicity. Multiple agents injected separately or in the form of activatable agents can be detected throughout the body for days to weeks after injection with no evident toxicity. In the proposed work, fluorescent contrast agents will be investigated that target cancer-specific cell-surface receptors and extracellular enzymes. The expression of these biomarkers will be monitored in relation to therapeutic response to develop quantitative methods that can be used for preclinical drug development and eventually translated to clinical use. Optical imaging results will be compared and combined with diffusion-weighted and contrast-enhanced magnetic resonance imaging data for synergistic cancer characterization. The combined training and preclinical imaging research will equip the Candidate with the expertise and experience to be a leader in the field of preclinical imaging research. PUBLIC HEALTH RELEVANCE (provided by applicant): The Candidate will receive training in cancer biology and biomedical imaging techniques through development of multimodal imaging approach to measure therapeutic response in animal models of breast cancer. Detection of therapeutic response early initiation can speed the clinical decision- making process and improve overall response. Non-invasive imaging techniques are needed for this purpose.